A traceback phenomenon can reveal the origin of prion infection

The transmission of prions to animals with incongruent prion protein (PrP) gene (referred to as cross‐sequence transmission) results in a relatively long incubation period and can generate a new prion strain with unique transmissibility designated as a traceback phenomenon. For example, cross‐sequence transmission of bovine spongiform encephalopathy (BSE) prions to human generated variant Creutzfeldt‐Jakob disease (vCJD) prions which retained the transmissibility to mice expressing bovine PrP. This finding suggests that traceback studies could enable us to identify the origin of prions. There are two distinct phenotypes in dura mater graft‐associated Creutzfeldt‐Jakob disease (dCJD), with the majority represented by a non‐plaque‐type of dCJD (np‐dCJD) and the minority by a plaque‐type of dCJD (p‐dCJD). To identify the origin of p‐dCJD, we performed a traceback study using mice expressing human PrP with methionine homozygosity (129M/M) or valine homozygosity (129V/V) at polymorphic codon 129. The characteristics of p‐dCJD such as the accumulation of abnormal isoform of PrP (PrP^Sc) intermediate in size between type 1 and type 2, and plaque‐type PrP deposition in the brain were maintained after transmission to the 129M/M mice. Furthermore, the 129V/V mice were more susceptible to p‐dCJD prions than the 129M/M mice and produced type 2 PrP^Sc that were identical in size to those from the 129V/V mice inoculated with sporadic CJD prions from a patient with 129V/V and type 2 PrP^Sc (sCJD‐VV2). In addition, we performed intracerebral transmission of sCJD‐VV2 prions to the 129M/M mice as an experimental model for p‐dCJD. These 129M/M mice showed the accumulation of the intermediate type PrP^Sc and plaque‐type PrP deposition in the brain. These results suggest that p‐dCJD could be caused by cross‐sequence transmission of sCJD‐VV2 prions to individuals with the 129M/M genotype.     

Dura mater graft‐associated Creutzfeldt‐Jakob disease in Japan: Clinicopathological and molecular characterization of the two distinct subtypes

Up to February 2008, a total of 132 patients with dura mater graft‐associated Creutzfeldt‐Jakob disease (dCJD) have been identified in Japan, accounting for a majority of the world's patients with dCJD. The patients received dura mater grafts from 1978 to 1993. Lyodura^® (B. Braun, Melsungen, Germany) was used for all the patients in whom the brand name of the dura mater could be identified. After the incubation period of 1 to 25 years (mean, 11.8 years), CJD appeared from 1985 through to 2006. We analyzed clinical, pathological, and molecular features in 74 patients with dCJD who had been prospectively registered by the CJD Surveillance Committee. The cases of dCJD could be classified into two distinct clinicopathological phenotypes: a non‐plaque type, showing typical features identical with those of classic CJD, and a plaque type, characterized by atypical features, including slow progression, lack of or late occurrence of periodic sharp wave complexes on EEG, and plaque formation in the brain. The plaque type accounted for one‐third of the pathologically confirmed or clinically diagnosed cases of dCJD. The non‐plaque type was associated with methionine homozygosity at codon 129 (129M/M) of the PrP gene in all patients, except for in one patient with the 129M/valine (V) genotype and type 1 protease‐resistant PrP (PrP^res), whereas the plaque type was always associated with the 129M/M genotype and the intermediate type between types 1 and 2 of PrP^res in all cases. Thus, the clinicopathological and molecular features of the plaque type are distinct from those of the non‐plaque type, suggesting contamination of the dura mater grafts with different prion strains.     

Accumulation of prion protein in the vagus nerve in creutzfeldt–jakob disease

Disease‐associated proteins are thought to propagate along neuronal processes in neurodegenerative diseases. To detect disease‐associated prion protein (PrP^Sc) in the vagus nerve in different forms and molecular subtypes of Creutzfeldt–Jakob disease (CJD), we applied 3 different anti‐PrP antibodies. We screened the vagus nerve in 162 sporadic and 30 genetic CJD cases. Four of 31 VV‐2 type sporadic CJD and 7 of 30 genetic CJD cases showed vagal PrP^Sc immunodeposits with distinct morphology. Thus, PrP^Sc in CJD affects the vagus nerve analogously to α‐synuclein in Parkinson disease. The morphologically diverse deposition of PrP^Sc in genetic and sporadic CJD argues against uniform mechanisms of propagation of PrP^Sc. Ann Neurol 2019;85:782–787     

A case of sporadic Creutzfeldt‐Jakob disease with both plaque and synaptic‐type deposition of prion protein

We report a Japanese case of sporadic Creutzfeldt‐Jakob disease (CJD) with particular clinical course and neuropathological findings. A 74‐year‐old female exhibited parkinsonism and later, dementia, myoclonus as well as visual hallucinations, lacking periodic synchronous discharges in the electroencephalogram. The duration of her illness was 2 years, longer than typical CJD cases which average 8 months’ duration. Gray matter was severely affected, the Ammon’s horn and subicular cortex were well preserved and many kuru plaques were observed in the cerebellum using routine histological stainings. Immunohistochemistry for prion protein (PrP) using both formic acid and hydrolytic autoclaving pretreatment revealed numerous prion plaques throughout the brain together with intense synaptic‐type deposition of PrP^CJD (abnormal isoform of PrP) in all gray matter examined, particularly in the Ammon’s horn and subicular cortex. The definite combination of these two types of stain has never been reported previously in Japan other than in Gerstmann‐Sträussler– Scheinker syndrome. Relative resistance of the Ammon’s horn and subicular cortex to the PrP^CJD deposition is also discussed.     

Clinicopathologic characteristics of five autopsied cases of dura mater‐associated Creutzfeldt‐Jakob disease

We present five cases of dura mater‐associated Creutzfeldt‐Jakob disease (dura‐CJD) that were analyzed clinicopathologically and review previous reports. The average age at dura mater transplantation was 54.4 ± 7.3 years, and the average age at CJD onset was 66.0 ± 8.2 years, with an average latency period of 11.6 ± 1.1 years. The average age at death was 67.6 ± 8.7 years, with an average CJD disease duration of 16.8 ± 10.4 months. Symptoms of CJD onset in four patients who received dura mater transplantation below the cerebellar tent reflected cerebellar or brainstem dysfunction, whereas symptoms of one patient who received transplantation above the cerebellar tent reflected cerebral cortical involvement. All patients showed rapidly progressive cognitive impairment, and both periodic sharp‐wave complexes on electroencephalogram and myoclonus were observed in the early disease stage. Neuropathologic evaluation showed one case of subacute spongiform encephalopathy and four cases of panencephalopathic‐type CJD. Widespread cerebral neocortical, subcortical gray matter and cerebellar cortical involvement were observed to varying degrees, and severity tended to be associated with CJD disease duration. There were no instances of kuru plaques or florid plaques. Prion protein (PrP) immunostaining showed widespread synaptic‐type PrP deposition. No differences between our dura‐CJD cases and typical cases of sporadic CJD were found with respect to clinicopathologic findings, except history of dura mater transplantation. Although a specific association between the dura mater graft site and neuropathologic observations was not evaluated in the present study, the initial symptoms appear to be closely related to the graft site, indicating a direct transmission of CJD from the graft site to the adjacent brain.     

Incidence and spectrum of sporadic Creutzfeldt–Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification

Six subtypes of sporadic Creutzfeldt–Jakob disease with distinctive clinico-pathological features have been identified largely based on two types of the abnormal prion protein, PrP^Sc, and the methionine (M)/valine (V) polymorphic codon 129 of the prion protein. The existence of affected subjects showing mixed phenotypic features and concurrent PrP^Sc types has been reported but with inconsistencies among studies in both results and their interpretation. The issue currently complicates diagnosis and classification of cases and also has implications for disease pathogenesis. To explore the issue in depth, we carried out a systematic regional study in a large series of 225 cases. PrP^Sc types 1 and 2 concurrence was detected in 35% of cases and was higher in MM than in MV or VV subjects. The deposition of either type 1 or 2, when concurrent, was not random and always characterized by the coexistence of phenotypic features previously described in the pure subtypes. PrP^Sc type 1 accumulation and related pathology predominated in MM and MV cases, while the type 2 phenotype prevailed in VVs. Neuropathological examination best identified the mixed types 1 and 2 features in MMs and most MVs, and also uniquely revealed the co-occurrence of pathological variants sharing PrP^Sc type 2. In contrast, molecular typing best detected the concurrent PrP^Sc types in VV subjects and MV cases with kuru plaques. The present data provide an updated disease classification and are of importance for future epidemiologic and transmission studies aimed to identify etiology and extent of strain variation in sporadic Creutzfeldt–Jakob disease.     

Autopsied case of sporadic Creutzfeldt–Jakob disease classified as MM1+2C‐type

We encountered an autopsy case of sporadic Creutzfeldt‐Jakob disease (CJD) pathologically classified as MM1+2C‐type, where Western blot analysis of prion protein (PrP) mainly showed type‐1 scrapie PrP (PrP^Sc) but also, partially, mixed type‐2 PrP^Sc. A Japanese woman complained of visual disorder at the age of 86 years and then showed disorientation and memory disturbances. Magnetic resonance imaging (MRI) showed cerebral cortical hyperintensity on diffusion‐weighted images. The patient died 2 months after the onset of symptoms; her condition did not reach the akinetic mutism state and periodic sharp‐wave complexes on electroencephalography and myoclonus were not recognized. The brain weighed 1100 g and neuropathological examination showed extensive fine vacuole‐type spongiform changes in the cerebral cortex. In some cortical regions, large confluent vacuole‐type spongiform changes were also present. Gliosis and hypertrophic astrocytosis were generally mild, and tissue rarefaction of the neuropil and neuronal loss were not apparent. PrP immunostaining showed diffuse synaptic‐type PrP deposition in the cerebral gray matter, but some regions with large confluent vacuoles showed perivacuolar‐type deposition. We speculated, based on the clinicopathological findings and previous reports, that most MM1‐type sporadic CJD cases may be associated with type‐2 PrP^Sc, at least partially, within certain regions of the cerebrum.     

Autopsy case of MV2K‐type sporadic Creutzfeldt‐Jakob disease with spongiform changes of the cerebral cortex

Comprehensive analysis is required for the accurate diagnosis of MV2‐type sporadic Creutzfeldt–Jakob disease (sCJD) because it shows a wide clinicopathological spectrum. Here, we describe the clinical findings and neuropathologic observations of an autopsy‐confirmed MV2K‐type sCJD case with extensive spongiform changes of the cerebral cortex. In the early disease stages, the patient exhibited gait disturbance with ataxia and gradually showed cognitive dysfunction. Diffusion‐weighted magnetic resonance images revealed hyperintense regions in the cerebral cortex, basal ganglia, and particularly in the thalamus. Prion protein (PrP) gene analysis revealed no mutations, and polymorphic codon 129 exhibited methionine and valine heterozygosity. During the course of the disease, a startle reaction was observed, whereas myoclonus was not observed. Electroencephalography showed no periodic sharp wave complexes. The patient died at age 61 years with 13 months total disease duration and did not reach the akinetic mutism state. Pathologic investigation revealed extensive fine vacuole‐type spongiform change in the cerebral cortex, and the appearance of vacuolation tended to be more pronounced in the deeper layers. Numerous kuru plaques were observed in the cerebellum. PrP immunostaining revealed extensive diffuse synaptic‐type PrP deposition in the cerebral cortex, and the finding was prominent in the deeper layer with perineuronal‐type PrP deposition. In the limbic system, basal ganglia, and thalamus, mixed small plaque‐type PrP with synaptic‐type PrP deposition was observed. In the cerebellar cortex, diffuse synaptic‐type PrP depositions were observed with numerous strongly immunopositive plaques. Western blot analysis of examined brain samples revealed mixed type 2 PrP^Sc (scrapie type) and intermediate‐type PrP^Sc.     

Protease‐resistant PrP and PrP oligomers in the brain in human prion diseases after intraventricular pentosan polysulfate infusion

Intraventricular infusion of pentosan polysulfate (PPS) as a treatment for various human prion diseases has been applied in Japan. To evaluate the influence of PPS treatment we performed pathological examination and biochemical analyses of PrP molecules in autopsied brains treated with PPS (one case of sporadic Creutzfeldt‐Jakob disease (sCJD, case 1), two cases of dura mater graft‐associated CJD (dCJD, cases 2 and 4), and one case of Gerstmann‐Sträussler‐Scheinker disease (GSS, case 3). Six cases of sCJD without PPS treatment were examined for comparison. Protease‐resistant PrP (PrP^res) in the frontal lobe was evaluated by Western blotting after proteinase K digestion. Further, the degree of polymerization of PrP molecules was examined by the size‐exclusion gel chromatography assay. PPS infusions were started 3–10 months after disease onset, but the treatment did not achieve any clinical improvements. Postmortem examinations of the treated cases revealed symmetrical brain lesions, including neuronal loss, spongiform change and gliosis. Noteworthy was GFAP in the cortical astrocytes reduced in all treated cases despite astrogliosis. Immunohistochemistry for PrP revealed abnormal synaptic deposits in all treated cases and further plaque‐type PrP deposition in case 3 of GSS and case 4 of dCJD. Western blotting showed relatively low ratios of PrP^res in case 2 of dCJD and case 3 of GSS, while in the treated sCJD (case 1), the ratio of PrP^res was comparable with untreated cases. The indices of oligomeric PrP were reduced in one sCJD (case 1) and one dCJD (case 2). Although intraventricular PPS infusion might modify the accumulation of PrP oligomers in the brains of patients with prion diseases, the therapeutic effects are still uncertain.     

Distinctive cerebellar immunoreactivity for the prion protein in familial (E200K) Creutzfeldt-Jakob disease

We have compared the immunomorphological spectrum of the deposition of the disease-associated prion protein (PrP(Sc)) in the cerebral and cerebellar cortex of 32 Creutzfeldt-Jakob disease (CJD) patients with the PrP gene (PRNP) E200K mutation to 45 sporadic CJD and 14 other genetic prion disease cases. PrP deposits correlate with the genotype at the methionine/valine (MV) polymorphic codon 129. While the diffuse/synaptic and patchy/perivacuolar PrP deposits and PrP plaques have a similar distribution and correlation with the genotype at codon 129 as in sporadic CJD, an additional peculiar PrP immunostaining pattern occurs in the cerebellum in 81% E200K mutation brains including 93% of M129M, 71% of M129V, but not in the single V129V case. It is localized to the molecular layer and consists of coarse granular PrP deposits arranged in a stripe-like manner predominantly perpendicular to the surface, closely resembling the parasagittal arborization of climbing fibers. Our results suggest that (1) the type of PrP deposits in the cerebellum may suggest genetic disease and the need for genetic testing; and (2) the peculiar stripes of PrP deposits might reflect selective vulnerability of cerebellar structures.     

Extensive cortical spongiform changes with cerebellar small amyloid plaques: The clinicopathological case of MV2K+C subtype in Creutzfeldt‐Jakob disease

We report a clinical case report of the MV2K+C subtype of sporadic Creutzfeldt‐Jakob disease (sCJD). The patient was a 72‐year‐old woman who exhibited progressive dementia over the course of 22 months. Diffusion‐weighted MRI during this period showed abnormal hyperintensity in the cerebral cortex in the early stage. The clinical course was similar to that of previously reported patients with the MV2K or MV2K+C subtype of sCJD. However, histopathological examination revealed unique features: severe extensive spongiform changes with perivacuolar deposits in the cerebrum and basal ganglia, plaque‐like PrP deposits in the cerebrum, and only mild changes in the cerebellum with small amyloid plaques (～20 μm in diameter), smaller than those in the MV2K subtype or variant CJD (40–50 μm in diameter). Molecular analysis showed a methionine/valine heterozygosity at codon 129 and no pathogenic mutation in the PrP gene (PRNP). Western blot analysis of the protease‐resistant PrP (PrP^Sc) in the right temporal pole revealed the type 2 pattern, which is characterized by a single unglycosylated band, in contrast to the doublet described for the typical MV2 subtype of sCJD. The other intermediate band might exist in the cerebellum with kuru plaques. Therefore, small amyloid plaques in the cerebellum can be crucial for MV2K+C subtype.     

Clusterin solubility and aggregation in Creutzfeldt-Jakob disease

Prion protein (PrP^C) is a glycolipid-anchored cell membrane syaloglycoprotein that localizes in presynaptic membranes. PrP has the property of aggregating into amyloid fibrils and being deposited in the brains in cases with transmissible encephalopathies (TSEs), when PrP^C is converted into abnormal protease-resistant PrP (PrP^RES). Clusterin is a heterodimeric glycoprotein, the expression of which is enhanced in astrocytes in association with punctate-type PrP^RES deposits during TSE progression. In addition, clusterin co-localizes in PrP^RES plaques in several human TSEs, including Creutzfeldt-Jakob disease (CJD). Clusterin is up-regulated in the cerebral cortex and cerebellum in CJD as revealed by DNA micro-array technology. Clusterin expression was examined in seven sporadic cases of CJD (codon 129 genotype, PrP type: 4 MM1, 1 MV1, 1 MV2, 1 VV2) and three age-matched controls by immunohistochemistry, Western blotting and solubility. In addition to small punctate clusterin deposition in the neuropil, single- and double-labeling immunohistochemistry disclosed clusterin localization in PrP^RES plaques, which predominated in the cerebellum of cases MV1, MV2 and VV2. Moreover, clusterin in plaques, but not punctate clusterin deposits, was resistant to protease digestion, as revealed in tissue sections pre-incubated with proteinase K. Clusterin in CJD, but not clusterin in control brains, was partially resistant to protease digestion in Western blots of total brain homogenates immunostained with anti-clusterin antibodies, which were processed in parallel with Western blots to PrP, without and with pre-incubation with proteinase K. Protein aggregation was analyzed in brain homogenates subjected to several solvents. PrP was recovered in the deoxycholate fraction in control and CJD cases, but in the SDS fraction only in CJD, thus indicating differences in PrP solubility between CJD and controls. Clusterin was recovered in the cytosolic, deoxycholate and SDS fraction in both CJD and control cases, but only clusterin from CJD was recovered in the urea-soluble fraction and, especially, in the remaining pellet. These findings demonstrate the capacity of clusterin to form aggregates and interact with PrP^RES aggregates. The implications of this property are not known, but it can be suggested that clusterin participates in PrP clustering and sequestration, thus modifying PrP toxicity in CJD.     

Molecular biology and pathology of prion strains in sporadic human prion diseases

Prion diseases are believed to propagate by the mechanism involving self-perpetuating conformational conversion of the normal form of the prion protein, PrP^C, to the misfolded, pathogenic state, PrP^Sc. One of the most intriguing aspects of these disorders is the phenomenon of prion strains. It is believed that strain properties are fully encoded in distinct conformations of PrP^Sc. Strains are of practical relevance to human prion diseases as their diversity may explain the unusual heterogeneity of these disorders. The first insight into the molecular mechanisms underlying heterogeneity of human prion diseases was provided by the observation that two distinct disease phenotypes and their associated PrP^Sc conformers co-distribute with distinct PrP genotypes as determined by the methionine/valine polymorphism at codon 129 of the PrP gene. Subsequent studies identified six possible combinations of the three genotypes (determined by the polymorphic codon 129) and two common PrP^Sc conformers (named types 1 and 2) as the major determinants of the phenotype in sporadic human prion diseases. This scenario implies that each 129 genotype–PrP^Sc type combination would be associated with a distinct disease phenotype and prion strain. However, notable exceptions have been found. For example, two genotype–PrP^Sc type combinations are linked to the same phenotype, and conversely, the same combination was found to be associated with two distinct phenotypes. Furthermore, in some cases, PrP^Sc conformers naturally associated with distinct phenotypes appear, upon transmission, to lose their phenotype-determining strain characteristics. Currently it seems safe to assume that typical sporadic prion diseases are associated with at least six distinct prion strains. However, the intrinsic characteristics that distinguish at least four of these strains remain to be identified.     

Infectious prion disease: CJD with dura mater transplantation]

Prion diseases include scrapie, BSE and CWD in animals, and spontaneous, familiar and infectious Creutzfeldt-Jakob disease(CJD) in human. Infectious prion diseases include kuru, variant CJD and iatrogenic CJD. CJD has been transmitted from human to human by contaminated cadaveric dura mater grafts and by cadaveric pituitary hormones. To date, CJD associated with dura mater grafts, reaching 156 cases, has been reported in 17 countries. More 2/3 of cases have been reported in Japan. Nationwide survey and recent information documented 105 dura-related cases during the period between 1979 and 2003. At least 91 cases received same brand of dura mater by a single German company. Age at disease onset in cases with dura-related CJD was younger (54.2 +/- 14.2 years) than sporadic CJD (64 +/- 10 years). Two groups of dura-related CJD are manifest in clinical course and pathological characteristics, such as rapidly progressive group and slowly progressive. Rapidly group was similar to cases with classical CJD in clinical features and shot duration to death from onset. Slowly progressive group developed akinetic mutism longer than 1 year, and characterized by florid plaques in the brain (Kitamoto).     

Sporadic Creutzfeldt-Jakob disease with MM1-type prion protein and plaques

The authors report a 75-year-old woman with atypical sporadic Creutzfeldt-Jakob disease (CJD) characterized by MM1-type prion protein (PrP) (methionine homozygosity at codon 129 in the PrP gene and type-1 protease-resistant PrP) and PrP plaques. This patient is the first case of sporadic CJD with plaque-forming MM1-type PrP, suggesting either a shared prion strain with the plaque-forming subset of dural graft-associated CJD or shared host genetic factors that are unrelated to the PrP genotype.     

Phenotypic variability of sporadic human prion disease and its molecular basis: past,present, and future

Human prion diseases are rare neurodegenerative disorders related to prion protein misfolding that can occur as sporadic, familial or acquired forms. In comparison to other more common neurodegenerative disorders, prion diseases show a wider range of phenotypic variation and largely transmit to experimental animals, a feature that led to the isolation and characterization of different strains of the transmissible agent or prion with distinct biological properties. Biochemically distinct PrP^Sc types have been demonstrated which differ in their size after proteinase cleavage, glycosylation pattern, and possibly other features related to their conformation. These PrP^Sc types, possibly enciphering the prion strains, together with the naturally occurring polymorphism at codon 129 in the prion protein gene have a major influence on the disease phenotype. In the sporadic form, the most common but perhaps least understood form of human prion disease, there are at least six major combinations of codon 129 genotype and prion protein isotype, which are significantly related to distinctive clinical–pathological subgroups of the disease. In this review, we provide an update on the current knowledge and classification of the disease subtypes of the sporadic human prion diseases as defined by molecular features and pathological changes. Furthermore, we discuss the molecular basis of phenotypic variability taking into account the results of recent transmission studies that shed light on the extent of prion strain variation in humans.     

Sporadic fatal insomnia with spongiform degeneration in the thalamus and widespread PrPSc deposits in the brain

We report a case of human prion disease of 29 months duration in a 74‐year‐old Japanese man. The disease started with progressive sleeplessness and dementia. MRI showed gradually progressive cerebral atrophy. Neuronal loss, spongiform change and gliosis were evident in the thalamus and cerebral cortex, as well as in the striatum and amygdaloid nucleus. In the cerebellar cortex, mild‐to‐moderate depletion of Pukinje cells and spongiform change were observed. Mild neuronal loss in the inferior olivary nucleus was also seen. Immunohistochemistry revealed widespread perivacuolar deposits of abnormal prion protein (PrP^Sc) in the cerebral cortex, thalamus, basal ganglia, and brainstem, and minimal plaque‐like deposits of PrP^Sc in the cerebellar cortex. In the cerebellar plaque‐like deposits, the presence of amyloid fibrils was confirmed ultrastructurally. The entire pathology appeared to lie halfway between those of CJD and fatal insomnia, and further demonstrated the relationship between spongiform degeneration and PrP^Sc deposits, especially in the diseased thalamus. By immunoblotting, the thalamus was shown to contain the lowest amount of PrP^SC among the brain regions examined. The PrP^Sc of type 2, in which the ratio of the three glycoforms was compatible with that of sporadic fatal insomnia (MM2‐thalamic variant) reported previously, was also demonstrated. Analysis of the prion protein gene (PRNP) showed no mutation, and homozygosity for methionine at codon 129. In conclusion, we considered that this patient had been suffering from sporadic, pathologically atypical fatal insomnia.     

Creutzfeldt‐Jakob disease

This review will explore the clinical and pathological findings of the various forms of Creutzfeldt‐Jakob disease (CJD). Clinical findings of CJD are characterized by rapidly progressive cognitive dysfunction, diffusion‐weighted magnetic resonance imaging (DWI) hyperintensity, myoclonus, periodic sharp‐wave complexes on electroencephalogram and akinetic mutism state. Neuropathologic findings of CJD are characterized by spongiform changes in gray matter, gliosis—particularly hypertrophic astrocytosis—neuropil rarefaction, neuron loss and prion protein (PrP) deposition. The earliest pathological symptom observed by HE staining in the cerebral cortex is spongiform change. This spongiform change begins several months before clinical onset, and is followed by gliosis. Subsequently, neuropil rarefaction appears, followed by neuron loss. Regions showing fine vacuole‐type spongiform change reflect synaptic‐type PrP deposition and type 1 PrP^Sc deposition, whereas regions showing large confluent vacuole‐type spongiform changes reflect perivacuolar‐type PrP deposition and type 2 PrP^Sc deposition. Hyperintensities of the cerebral gray matter observed in DWI indicate the pathology of the spongiform change in CJD. The cerebral cortical lesions with large confluent vacuoles and type 2 PrP^Sc show higher brightness and more continuous hyperintensity on DWI than those with fine vacuoles and type 1 PrP^Sc. CJD cases showing diffuse myelin pallor of cerebral white matter have been described as panencephalopathic‐type, and this white matter pathology is mainly due to secondary degeneration caused by cerebral cortical involvement, particularly in regard to neuron loss. In conclusion, clinical and neuroimaging findings and neuropathologic observations are well matched in both typical and atypical cases in CJD. The clinical diagnosis of CJD is relatively easy for typical CJD cases such as the MM1‐type. However, even in atypical cases it seems that clinical findings can be used for an accurate diagnosis.     

Autopsied case of non‐plaque‐type dura mater graft‐associated Creutzfeldt‐Jakob disease presenting with extensive amyloid‐β deposition

We present an autopsied case of non‐plaque‐type dura mater graft‐associated Creutzfeldt‐Jakob disease (dCJD) with extensive amyloid‐β (Aβ) deposition in the brain. A 39‐year‐old Japanese woman presented with memory disturbance and abnormal behavior. The patient had a history of craniotomy with dura matter‐graft transplant for a head injury which occurred when she was 19 years old. Magnetic resonance imaging (MRI) showed hyperintensities in the cerebral cortex and striatum on diffusion‐weighted images, particularly on the dura mater‐grafted right side. Her clinical symptoms, including rapidly progressing cognitive impairment, myoclonus, and periodic sharp wave complexes on electroencephalogram, could not be distinguished from typical sporadic CJD cases. The patient died 11 months after symptom onset, and pathological investigations showed extensive spongiform degeneration with prion protein (PrP) deposition without Kuru plaques; these observations were essentially the same as those of typical sporadic CJD cases. Furthermore, Aβ immunohistochemistry showed extensive diffuse staining in the cerebral neocortex, plaque‐type deposition, positive staining in the pia mater, and cerebral amyloid angiopathy. Although the MRI findings suggested that the pathological involvement originated from the dura mater‐grafted right side, the PrP and Aβ depositions showed no apparent regionalization and laterality. Tau‐pathology including neurofibrillary tangles was hardly identified. The proteins phosphorylated α‐synuclein and phosphorylated transactivation response DNA‐binding protein 43 kDa were not detected on immunostaining. Although this report describes only one case, various speculations were made based on detailed clinical and pathological observations in conjunction with previous reports of dCJD. In particular, this report provides significant insight into the characteristics and progression of dCJD pathology and its relationship with Aβ pathology.     

A novel seven-octapeptide repeat insertion in the prion protein gene (PRNP) in a Dutch pedigree with Gerstmann�CStr?ussler�CScheinker disease phenotype: comparison with similar cases from the literature

Human prion diseases can be sporadic, inherited or acquired by infection and show considerable phenotypic heterogeneity. We describe the clinical, histopathological and pathological prion protein (PrP^Sc) characteristics of a Dutch family with a novel 7-octapeptide repeat insertion (7-OPRI) in PRNP, the gene encoding the prion protein (PrP). Clinical features were available in four, neuropathological features in three and biochemical characteristics in two members of this family. The clinical phenotype was characterized by slowly progressive cognitive decline, personality change, lethargy, depression with anxiety and panic attacks, apraxia and a hypokinetic-rigid syndrome. Neuropathological findings consisted of numerous multi- and unicentric amyloid plaques throughout the cerebrum and cerebellum with varying degrees of spongiform degeneration. Genetic and molecular studies were performed in two male family members. One of them was homozygous for valine and the other heterozygous for methionine and valine at codon 129 of PRNP. Sequence analysis identified a novel 168?bp insertion [R2?CR2?CR2?CR2?CR3g?CR2?CR2] in the octapeptide repeat region of PRNP. Both patients carried the mutation on the allele with valine at codon 129. Western blot analysis showed type 1 PrP^Sc in both patients and detected a smaller ~8?kDa PrP^Sc fragment in the cerebellum in one patient. The features of this Dutch kindred define an unusual neuropathological phenotype and a novel PRNP haplotype among the previously documented 7-OPRI mutations, further expanding the spectrum of genotype?Cphenotype correlations in inherited prion diseases.